Osteosarcoma is a primary bone malignancy with a high rate of recurrence and poorer prognosis. Therefore, it is of vital importance to explore novel prognostic molecular biomarkers and targets for more effective therapeutic approaches. Previous studies showed that histone demethylase KDM5A can increase the proliferation and metastasis of several cancers. However, the function of KDM5A in the carcinogenesis of osteosarcoma is not clear. In the current study, KDM5A was highly expressed in osteosarcoma than adjacent normal tissue. Knockdown of KDM5A suppressed osteosarcoma cell proliferation and induced apoptosis. Moreover, knockdown of KDM5A could increase the expression level of P27 (cell-cycle inhibitor) and decrease the expression of Cyclin D1. Furthermore, after knockout of KDM5A in osteosarcoma cells by CRISPR/Cas9 system, the tumor size and growth speed were inhibited in tumor-bearing nude mice. RNA-Seq of KDM5A-KO cells indicated that interferon, epithelial–mesenchymal transition (EMT), IL6/JAK/STAT3, and TNF-α/NF-κB pathway were likely involved in the regulation of osteosarcoma cell viability. Taken together, our research established a role of KDM5A in osteosarcoma tumorigenesis and progression.